This mentored career-development award will support Dr. Cynthia Brown as she continues to advance her career goal of becoming an independent patient-oriented researcher. Her specific area of interest is in sleep disorders in chronic lung disease, and the period of time covered by the career development award is important for Dr. Brown to acquire the necessary skills to become successful in this research area while continuing in a closely mentored relationship. During the period of this career development award, Dr. Brown will acquire additional experience in clinical trial design, data collection, and statistical analysis in addition to gaining new skills in the quantitative analysis of respiratory data during sleep. Dr. Brown will also learn how to collect and interpret nocturnal blood pressure analysis and biomarkers of neurohormonal activation and systemic inflammation. In order to further her skills, Dr. Brown will work closely with her mentorship committee to assure that she is meeting appropriate milestones both within the context of this project as well as with her long-term career goal of becoming an independent clinical research. To this end, this award will also provide support for Dr. Brown as she completes a Master's Degree in Clinical Research. Dr. Brown's expectations during the period covered by this award are to acquire these skills while generating important insights to her clinical project described below. This will allow Dr. Brown to become a competitive candidate for independent research funding in an area that overlaps multiple disciplines and creates an area of expertise for Dr. Brown independent of her mentors. The primary goal of the research is to better understand the mechanisms and consequences of sleep- disordered breathing in chronic obstructive pulmonary disease (COPD). Even in the absence of obstructive sleep apnea, sleep fragmentation and gas exchange abnormalities are common in COPD with consequent complaints of daytime fatigue. Preliminary data suggest that individuals with COPD are unable to compensate for small degrees of inspiratory resistance with consequent development of hypoventilation and sleep fragmentation without frank apneas and hypopneas. To date, no published research has investigated the consequences of sleep-disordered breathing and sleep fragmentation on systemic inflammation and the neurohormonal axis in COPD. Although no prior research has investigated the consequences of sleep-disordered breathing on systemic inflammation in COPD, obstructive sleep apnea is associated with similar disruptions to sleep continuity and nocturnal oxygenation. In obstructive sleep apnea, nocturnal hypertension and systemic inflammation have been associated with the degree of hypoxemia and sleep-disordered breathing. The specific aims of this proposal are: 1) to better understand how normal changes in inspiratory resistance during sleep affect sleep quality and ventilation;2) to ascertain whether sleep fragmentation and nocturnal hypoxemia lead to changes in sympathetic activation and systemic inflammation;and 3) to determine whether alleviating inspiratory resistance leads to improved sleep quality and ventilation. This study will enroll 57 individuals with moderate to severe COPD and 57 controls subjects in a case-control study to compare sleep continuity and respiratory patterns during sleep in response to changes in inspiratory resistance. In addition, this study will compare case and controls to assess whether individuals with COPD have evidence of higher nocturnal blood pressure and increased markers of sympathetic activation and systemic inflammation. Individuals with COPD will undergo further evaluation with use of nocturnal nasal insufflation (NNI). NNI delivers heated and humidified air at high flow rates to generate small degrees of positive nasal pressure. In preliminary investigations, this device has been shown to alleviate inspiratory flow limitation. This study will determine how use of NNI affects ventilation during sleep and overall sleep quality and may lead to further investigation of NNI as a novel treatment of sleep-disordered breathing in COPD. PUBLIC HEALTH RELEVANCE: Project Relevance COPD affects over 12 million individuals in the United States and is the 4th leading cause of death. In individuals with COPD, sleep complaints are prominent, but are poorly understood and treated. This research will lead to new insights into the causes of poor sleep quality in COPD and will provide important information about how disturbed sleep and oxygenation at night may lead to increased inflammation and changes in the sympathetic nervous system. Finally, this research studies a new intervention to determine if it might help to improve sleep quality in COPD. (End of Abstract)